WO2022258002A1 - Composé et procédé de traitement d'effets secondaires gastro-intestinaux associés à la chimiothérapie - Google Patents

Composé et procédé de traitement d'effets secondaires gastro-intestinaux associés à la chimiothérapie Download PDF

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WO2022258002A1
WO2022258002A1 PCT/CN2022/097793 CN2022097793W WO2022258002A1 WO 2022258002 A1 WO2022258002 A1 WO 2022258002A1 CN 2022097793 W CN2022097793 W CN 2022097793W WO 2022258002 A1 WO2022258002 A1 WO 2022258002A1
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alkylene
use according
hours
compound
formula
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PCT/CN2022/097793
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Chinese (zh)
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李文晰
刘世岚
吴兆宇
张诗宜
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上海岸阔医药科技有限公司
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Priority to CN202280041120.9A priority Critical patent/CN117545483A/zh
Priority to KR1020247000566A priority patent/KR20240021214A/ko
Priority to JP2023575985A priority patent/JP2024521441A/ja
Priority to EP22819599.6A priority patent/EP4353231A1/fr
Publication of WO2022258002A1 publication Critical patent/WO2022258002A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present application relates to the field of biomedicine, in particular to a method for preventing, alleviating and/or treating chemotherapy-related gastrointestinal side effects.
  • Tumor chemotherapy is one of the most commonly used means to treat tumors clinically. It mainly uses chemical drugs (chemotherapeutics) to prevent the proliferation, invasion, and metastasis of cancer cells until it finally kills cancer cells.
  • chemotherapeutics chemical drugs
  • the administration of chemotherapeutic agents can not only kill rapidly growing and detached tumor cells, but may also kill normal cells and immune cells together, thus causing serious side effects, including nausea, vomiting, anemia, inflammation and infection, etc. These side effects will lead to the withdrawal of chemotherapeutic agents or the reduction of the dose, which will greatly affect the patient's tumor treatment effect, and will impair the patient's quality of life, and in severe cases, endanger the patient's life.
  • the application provides a method for preventing, alleviating and/or treating chemotherapy-related gastrointestinal side effects (for example, diarrhea, enteritis or constipation) in a subject, the method comprising administering a compound represented by formula I to the subject or a pharmaceutically acceptable salt thereof.
  • the compound represented by formula I of the present application or a pharmaceutically acceptable salt thereof can effectively prevent, relieve and/or treat chemotherapy-related gastrointestinal side effects.
  • the application provides the use of a compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing, alleviating and/or treating chemotherapy-related gastrointestinal Road side effects:
  • Z is -(CH2) X -, wherein X is 1, 2, 3 or 4, or -O-(CH2) Z -, wherein z is 2, 3 or 4;
  • X and X' are each independently CH or N;
  • R, R 8 and R 11 are each independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S, - (Alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclyl, -(alkylene) m -heteroaryl , -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)-NR 3 R 4 , -(alkylene) m -OR 5 , -(alkylene) m -S(O)nR 5 , or -(alkylene) m -S(O) n -NR 3 R 4 , either of which can optionally be independently modified by one or more R The group is substituted, and
  • R is independently aryl, alkyl, cycloalkyl, or haloalkyl, wherein each of said alkyl, cycloalkyl, and haloalkyl optionally includes O or N in the chain instead of carbon heteroatom and two R on adjacent ring atoms or on the same ring atom, together with the ring atom to which they are attached, optionally form a 3-8 membered ring;
  • y is 0, 1, 2, 3 or 4;
  • R 2 is -(alkylene) m -heterocyclyl, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C( O)-NR 3 R 4 , -(alkylene) m -C(O)-O-alkyl; -(alkylene) m -OR 5 , -(alkylene) m -S(O) n -R or - (alkylene) m -S(O) n - NR3R4 , either of which may be optionally independently substituted with one or more Rx groups as valence permits, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring, and wherein m is 0 or 1 and n is 0, 1 or 2;
  • R 3 and R 4 are independently:
  • Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which are allowed by the valence may be optionally independently substituted with one or more R groups, and wherein two R groups bound to the same or adjacent atoms may optionally combine to form a ring ; or R and R Together with the nitrogen atoms to which they are attached, may combine to form a heterocyclic ring optionally independently substituted with one or more Rx groups as valency permits, and wherein two Rx groups bonded to the same or adjacent atoms may be optionally combined to form a ring;
  • alkyl alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl or heteroarylalkyl, wherein Either may be optionally substituted independently with one or more R groups as valency permits;
  • R x is independently halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, Heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene -OR 5 , -(alkylene) m -S(O) n -R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)-R 5 , -(alkylene) m -C(S)-R 5 , -(alkylene) m -C(O)-OR
  • alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkyl groups may be further independently substituted by one or more of the following groups:
  • n 0, 1 or 2
  • m 0 or 1
  • R3 * and R4 * are independently:
  • alkyl alkenyl, alkynylcycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl or heteroarylalkyl, any of which One may be optionally substituted independently with one or more R x groups as valence permits; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may be combined to form optionally are heterocycles independently substituted with one or more R x groups; and
  • R 6 is H or lower alkyl, -(alkylene) m -heterocyclyl, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene - ( alkylene) m -OR 5 , -(alkylene) m -S(O) n -R 5 or - ( alkylene) m - S(O) n -NR 3 R 4 , any of which may be optionally substituted independently by one or more R x groups as valence permits, and two of which are bound to the same or adjacent atoms R x groups can optionally combine to form a ring;
  • the pharmaceutically acceptable salt of the compound represented by formula I is hydrochloride.
  • the compound has the structure of Formula I and R is absent.
  • said R x in said formula I is not further substituted.
  • the R 8 in the formula I is hydrogen or C 1 -C 3 alkyl.
  • the R 11 in the formula I is hydrogen or C 1 -C 3 alkyl.
  • the compound comprises a compound shown in Formula Ia:
  • the X in the formula I or formula Ia is C.
  • the X' in the formula I or formula Ia is N.
  • the R in the formula I or formula Ia is hydrogen or C 1 -C 3 alkyl.
  • the R 2 in the formula I or formula Ia is -(alkylene) m -heterocyclyl, -(alkylene) m -NR 3 R 4 , -(alkylene group) m -C(O)-NR 3 R 4 , -(alkylene) m -C(O)-O-alkyl or -(alkylene) m -OR 5 , any of which is allowed by the valence may be optionally independently substituted with one or more R x groups, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring, and wherein m is 0 or 1.
  • the R 2 in the formula I or formula Ia is -(alkylene) m -heterocyclyl, -(alkylene) m -NR 3 R 4 , -(alkylene group) m -C(O)-NR 3 R 4 , -(alkylene) m -C(O)-O-alkyl or -(alkylene) m -OR 5 , without further substitution.
  • m in the R 2 in the formula I or formula Ia is 1.
  • the alkylene group in the R in the formula I or formula Ia is methylene.
  • the R in the formula I or formula Ia is Wherein, R2 * is a bond, alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m - , -(alkylene) m -S(O) 2 -(alkylene) m -and -(alkylene) m -NH-(alkylene) m -, wherein each m is independently 0 or 1;
  • P is a 4-8 membered monocyclic or bicyclic saturated heterocyclic group
  • each R x1 is independently -(alkylene) m -(C(O)) m -(alkylene) m -(N(R N )) m -(alkyl) m , wherein each m is independently is 0 or 1, provided that at least one m is 1; -(C(O))-O-alkyl; -(alkylene) m -cycloalkyl, wherein m is 0 or 1; -N( R N )-cycloalkyl; -C(O)-cycloalkyl; -(alkylene) m -heterocyclyl, wherein m is 0 or 1; or -N(R N )-heterocyclyl;- C(O)-heterocyclyl; -S(O) 2 -(alkylene) m , where m is 1 or 2, where:
  • RN is H, C 1 to C 4 alkyl, or C 1 to C 6 heteroalkyl
  • R x1 may form a ring together with the atoms to which they are attached on P which may be the same atom;
  • t 0, 1 or 2.
  • each of said R x 1 in said R 2 is optionally substituted with unsubstituted alkyl, halogen, or hydroxy.
  • R x1 in R 2 is hydrogen or unsubstituted C 1 -C 4 alkyl.
  • At least one of said R x1 of said R 2 is -(alkylene) m -heterocyclyl, wherein m is 0 or 1.
  • the R in the formula I or formula Ia is Wherein P* is a 4-8 membered monocyclic or bicyclic saturated heterocyclic group.
  • the R in the formula I or formula Ia is
  • the R in the formula I or formula Ia is
  • R 2* is a bond, alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m - , -(alkylene) m -S(O) 2 -(alkylene) m -and -(alkylene) m -NH-(alkylene) m -, wherein each m is independently 0 or 1;
  • P is 4 to 8 membered monocyclic or bicyclic and heterocyclic groups
  • P1 is a 4 to 6 membered monocyclic saturated heterocyclyl
  • each RX2 is independently hydrogen or alkyl; and s is 0, 1 or 2.
  • the R in the formula I or formula Ia is
  • P1 in said R2 includes at least one nitrogen.
  • any alkylene group in R 2* in any of the above embodiments is not further substituted.
  • said R 2 * in said R 2 is a bond.
  • said R x1 in said R 2 is hydrogen, methyl or propyl.
  • the R 2 is
  • the compound is selected from the group consisting of:
  • the compound is and its hydrochloride form.
  • the compound is and its hydrochloride form.
  • the chemotherapy comprises administering a chemotherapeutic agent.
  • the chemotherapeutic agent is a cytotoxic agent.
  • the chemotherapeutic agent is selected from one or more of the following group: DNA synthesis inhibitors, RNA synthesis inhibitors, protein synthesis inhibitors, cell division inhibitors, DNA base analogs, topological Isomerase inhibitors and/or telomerase synthesis inhibitors.
  • the chemotherapy is used in combination with one or more other therapies.
  • the chemotherapeutic agent is selected from the group consisting of fluorouracil, oxaliplatin, irinotecan, topotecan, etoposide, cisplatin, docetaxel, gemcitabine, carboplatin, methylamine Pterin, doxorubicin, cytarabine, vinorelbine, and capecitabine, and combinations thereof.
  • the chemotherapeutic agent is selected from 5-fluorouracil, irinotecan, and oxaliplatin, and combinations thereof.
  • the chemotherapy-related gastrointestinal side effects include gastrointestinal side effects caused by chemotherapeutic agents.
  • chemotherapy-related gastrointestinal side effects include gastrointestinal adverse events that occur or are exacerbated after administration of a chemotherapeutic agent.
  • the gastrointestinal adverse event occurs after about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours after administration of the chemotherapeutic agent without prophylaxis or treatment.
  • the gastrointestinal adverse event occurs after about 6 hours, after about 7 hours, after about 8 hours, after about 9 hours, after about 10 hours, after about 11 hours, after about 12 hours, after about 1 day, after about 2 days, after about 4 days, Appear or worsen after about 7 days, about 2 weeks, about 3 weeks, about 1 month, about 2 months or more.
  • the gastrointestinal side effects include gastric mucosal injury diseases and/or intestinal mucosal injury diseases.
  • the gastrointestinal side effects include diarrhea, abdominal pain, nausea, vomiting, mucositis, loss of appetite, gastric ulcer, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulceration and/or intestinal necrosis.
  • the gastrointestinal side effects include diarrhea, constipation and/or enteritis.
  • the severity of the gastrointestinal side effects is grade 1 or above, grade 2 or above, grade 3 or above, grade 4 or above according to NCI-CTCAE , or level 5.
  • the subject comprises a cancer patient.
  • the drug does not substantially affect the therapeutic effect of the chemotherapeutic agent.
  • the drug is administered about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours before the chemotherapy is administered. hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours or Dosing for longer.
  • the drug is administered about 0.5 to 12 hours before the chemotherapy.
  • the medicament is formulated for oral administration.
  • the medicament is formulated for administration by injection.
  • the medicament is formulated for subcutaneous, intramuscular, intraperitoneal and/or intravenous administration.
  • the medicament also includes one or more other active ingredients.
  • the present application provides a method for preventing, alleviating and/or treating gastrointestinal side effects associated with chemotherapy, which comprises administering the compound represented by the formula I or its pharmaceutically acceptable of salt.
  • the present application provides the compound represented by the formula I or a pharmaceutically acceptable salt thereof, which is used for preventing, alleviating and/or treating chemotherapy-related gastrointestinal side effects in a subject.
  • the present application provides a pharmaceutical combination, which includes the compound represented by formula I or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent.
  • the present application provides a kit comprising the compound represented by formula I or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent.
  • Fig. 1 has shown the diarrhea photograph of typical mouse of chemotherapeutic agent group in embodiment 1-201.
  • Figure 2 shows the results of partial diarrhea grades of the control group, chemotherapeutic agent group, and compound group represented by formula I in Examples 1-201.
  • Fig. 3 shows the number and shape photos of feces in the control group, chemotherapeutic agent group, and compound group represented by formula I in Examples 202-364.
  • Fig. 4 shows the partial stool reduction rate results of the chemotherapeutic agent group and the compound group represented by formula I in Examples 202-364.
  • Fig. 5 shows the results of partial diarrhea grades of the control group, chemotherapeutic agent group, and compound group represented by formula I in Examples 365-384.
  • Fig. 6 shows the partial stool reduction rate results of the chemotherapeutic agent group and the compound group represented by formula I in Examples 385-405.
  • alkyl when used alone or in other terms such as “haloalkyl” and “alkylamino” generally refers to a straight chain having from one to about twelve carbon atoms. or branched chain groups.
  • “Lower alkyl” generally means having one to about six carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, and the like.
  • alkylene encompasses bridged divalent straight and branched chain alkyl groups. Examples may include methylene, ethylene, propylene, isopropylene, and the like.
  • alkenyl generally refers to a straight or branched chain group having at least one carbon-carbon double bond and two to about twelve carbon atoms. "Lower alkenyl” has two to about six carbon atoms. Examples of alkenyl groups include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl and lower alkenyl encompass groups having "cis” and "trans” orientations or "E” and "Z” orientations.
  • alkynyl generally refers to a straight or branched chain group having at least one carbon-carbon triple bond and having two to about twelve carbon atoms. "Lower alkynyl” has two to about six carbon atoms. Examples of such groups include propargyl, butynyl, and the like. Alkyl, alkenyl, and alkynyl groups may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclyl, and the like.
  • alkylamino generally covers “N-alkylamino” and “N,N-dialkylamino", wherein the amino groups are independently substituted with one and two alkyl groups, respectively.
  • “Lower alkylamino” generally means having one or two alkyl groups having one to six carbon atoms attached to a nitrogen atom. Suitable alkylamino groups may be mono- or dialkylamino groups, such as N-methylamino, N-ethylamino, N,N-dimethylamino or N,N-diethylamino.
  • halo generally refers to a halogen, such as a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl generally refers to a group in which any one or more of the alkyl carbon atoms are substituted by one or more halo groups. Examples may include monohaloalkyl, dihaloalkyl, and polyhaloalkyl, including perhaloalkyl.
  • a monohaloalkyl group can have iodo, bromo, chloro, or fluoro atoms within the group.
  • Dihaloalkyl and polyhaloalkyl groups can have two or more than two of the same halo atoms or a combination of different halo groups.
  • “Lower haloalkyl” may encompass groups having 1-6 carbon atoms.
  • haloalkyl groups may include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl , dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perfluoroalkyl generally refers to an alkyl group in which all hydrogen atoms are replaced by fluorine atoms, and examples may include trifluoromethyl and pentafluoroethyl.
  • aryl alone or in combination with other terms generally refers to a carbocyclic aromatic system containing one or two rings, wherein such rings may be attached together in a fused fashion.
  • aryl generally refers to an aromatic group such as phenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl. A more preferred aryl is phenyl.
  • the "aryl” may have one or more substituents such as lower alkyl, hydroxy, halo, haloalkyl, nitro, amino, alkoxy, lower alkylamino and the like.
  • Aryl groups can be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclyl, and the like.
  • heterocyclyl generally refers to saturated and partially saturated heteroatom-containing ring groups, wherein the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • Heterocycles include monocyclic 6-8 membered rings as well as 5-16 membered bicyclic ring systems (which may include bridge-fused and spiro-fused bicyclic systems). It does not include rings containing -O-O-, -O-S- or -S-S- moieties.
  • heterocyclic group may have 1 to 3 substituents, such as hydroxyl, Boc, halo, haloalkyl, amino, lower alkyl, lower aralkyl, oxo, lower alkoxy, Amino, lower alkylamino and the like.
  • saturated heterocyclic groups include saturated 3 to 6 membered heteromonocyclic groups (such as pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl) containing 1 to 4 nitrogen atoms; 2 oxygen atoms and 1 to 3 nitrogen atoms saturated 3 to 6 membered heteromonocyclic group (such as morpholinyl); 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms Cyclic groups (eg thiazolidinyl).
  • partially saturated heterocyclic groups include dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl and the like.
  • partially saturated and saturated heterocyclic groups may include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl , Dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, Isochromanyl, chromanyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a] I
  • Heterocyclic groups also include condensed/condensed groups of heterocyclic groups and aryl groups: condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolazinyl, benzimidazole yl, quinolinyl, isoquinolyl, indazolyl, benzotriazolyl, tetrahydropyridazinyl (e.g.
  • tetrazolo[l,5-b]pyridazinyl containing 1 to 2 oxygen atoms
  • Unsaturated condensed heterocyclic groups with 1 to 3 nitrogen atoms for example, benzoxazolyl, benzoxadiazolyl
  • unsaturated condensed heterocyclic groups with 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g. benzothiazolyl, benzothiadiazolyl
  • saturated, partially unsaturated and unsaturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms e.g. benzofuryl, benzothienyl , 2,3-dihydrobenzo[1,4]dioxanyl and dihydrobenzofuranyl).
  • heteroaryl generally refers to an aryl ring system containing one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom Optionally quaternized.
  • Examples include unsaturated 5 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, Pyrazinyl, pyridazinyl, triazolyl (such as 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl); Unsaturated 5- to 6-membered heteromonocyclic groups containing oxygen atoms, such as pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing sulfur atoms, such as 2-thiophene group, 3-thienyl group, etc.; unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as o
  • thiazolyl such as 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, Azolyl.
  • heteroarylalkyl generally refers to an alkyl group substituted with a heteroaryl group. Examples include pyridylmethyl and thienylethyl.
  • sulfonyl whether used alone or in combination with other terms, such as in alkylsulfonyl, corresponds to the divalent group -SO 2 -.
  • carboxy (or carboxyl) whether used alone or in combination with other terms, such as “carboxyalkyl”, means -C(O)-OH.
  • carbonyl whether used alone or in combination with other terms, such as “aminocarbonyl”, means -C(O)-.
  • aminocarbonyl generally refers to an amide group of formula -C(O) -NH2 .
  • heterocycloalkyl generally refers to an alkyl group substituted with a heterocyclyl group. Examples include piperidinylmethyl and morpholinylethyl.
  • arylalkyl generally refers to an alkyl group substituted with an aryl group. Examples include benzyl, benzhydryl and phenethyl.
  • the aryl group in said arylalkyl group may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.
  • cycloalkyl generally refers to a saturated carbocyclic group having 3 to 10 carbons.
  • Lower cycloalkyl includes C3-C6 rings. Examples include cyclopentyl, cyclopropyl and cyclohexyl.
  • Cycloalkyl groups may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclyl, and the like.
  • cycloalkylalkyl generally refers to an alkyl group substituted with a cycloalkyl group.
  • “Lower cycloalkylalkyl” is a cycloalkyl group attached to an alkyl group having one to six carbon atoms. Examples include cyclohexylmethyl. Cycloalkyl groups in said groups may additionally be substituted with halo, alkyl, alkoxy and hydroxy.
  • cycloalkenyl includes carbocyclic groups having one or more carbon-carbon double bonds, including “cycloalkyladienyl” compounds. Examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.
  • oxo generally refers to an oxygen atom attached with a double bond.
  • nitro generally refers to -NO2 .
  • cyano generally refers to -CN.
  • the term “prodrug” generally refers to a compound that is converted to the parent drug when administered to a subject in vivo.
  • the term “parent drug” generally refers to any drug of the present application that is suitable for treating any condition in a subject, such as a human, or controlling or ameliorating the underlying cause or symptoms associated with any physiological or pathological condition described herein. said compound.
  • Prodrugs can be used to achieve any desired effect, including enhancing the properties of the parent drug or improving the pharmacokinetic or pharmacokinetic properties of the parent drug.
  • Prodrug strategies exist that provide a choice of conditions that modulate the in vivo production of the parent drug, all are considered to be encompassed herein.
  • Non-limiting examples of prodrug strategies include covalent attachment of removable groups or removable moieties of groups such as, but not limited to, acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, Amidation, reduction, oxidation, esterification, alkylation, other carboxyl derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydrides.
  • chemotherapeutic agents generally refers to a therapy for the treatment of tumors using chemotherapeutic agents that cause the death of cancer cells or interfere with the division, repair, growth and/or function of cancer cells.
  • the chemotherapeutic agents include chemical or biological substances capable of causing cancer cell death or interfering with the growth, division, repair and/or function of cancer cells.
  • the chemotherapeutic agents may include cytotoxic, cytostatic and antineoplastic agents that kill, inhibit the growth or metastasis of tumor cells or disrupt the cell cycle of rapidly proliferating cells.
  • Chemotherapeutic agents include natural compounds found in plants and animals, or man-made chemicals.
  • the chemotherapeutic agent is less selective for tumor cells and normal cells, so it can also interfere with the growth, division, repair and/or function of normal cells (such as bone marrow cells, hair follicle cells or digestive tract cells) , resulting in the death of normal cells.
  • the chemotherapeutics described in the present application may not include tumor-targeted drugs, that is, the chemotherapeutics described in the present application may not include proteins that can specifically recognize tumor cells, tumor tissues, tumor organs, or tumor cells (for example, tumor-associated antigen or tumor-specific antigen). Due to genetic mutations or other factors, certain kinases or phosphokinases are activated, leading to the proliferation of cancer cells.
  • the chemotherapeutic agents described herein also do not include those kinase inhibitors that inhibit abnormally activated kinases to prevent the division of cancer cells. Chemotherapeutic agents described herein also do not include antibodies and/or angiogenesis inhibitors.
  • examples of chemotherapy may include, but are not limited to, alkylating agents such as nitrogen mustards, ethyleneimine compounds, alkylsulfonates, and other compounds with alkylating effects such as nitrosoureas, Cisplatin and dacarbazine; antimetabolites such as folic acid, purine or pyrimidine antagonists; mitotic inhibitors such as vinca alkaloids and podophyllotoxin derivatives; cytotoxic antibiotics and camptothecin derivatives.
  • alkylating agents such as nitrogen mustards, ethyleneimine compounds, alkylsulfonates, and other compounds with alkylating effects such as nitrosoureas, Cisplatin and dacarbazine
  • antimetabolites such as folic acid, purine or pyrimidine antagonists
  • mitotic inhibitors such as vinca alkaloids and podophyllotoxin derivatives
  • cytotoxic antibiotics and camptothecin derivatives may include, but are not limited to, alkyl
  • Chemotherapy may also include amifostine, cisplatin, dacarbazine (DTIC), dactinomycin, streptomycin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin, Doxorubicin liposomal, gemcitabine, erythromycin, daunorubicin liposomal procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil (5- FU), vinblastine, vincristine, bleomycin, paclitaxel, docetaxel, adesleukin, asparaginase, busulfan, carboplatin, cladribine, camptothecin, irinotecan, 10-Hydroxy-7-ethyl-camptothecin (SN38), floxuridine, fludarabine, hydroxyurea, ifosfamide, idarubi
  • cytotoxic agent generally refers to an agent that inhibits a biological process of a cell or reduces the viability or proliferative potential of a cell. Cytotoxic agents can act in a variety of ways, such as, but not limited to, by inducing DNA damage, inducing cell cycle arrest, inhibiting DNA synthesis, inhibiting transcription, inhibiting translation or protein synthesis, inhibiting cell division, or inducing apoptosis.
  • the term "serial administration” generally refers to repeated administration of the same drug of the same type every day. Repeated daily administration can be once a day, twice a day, three times a day or more.
  • continuous administration may be administered once a day for at least 2 days or more.
  • the continuous administration period of 2 days may refer to the administration once a day (twice, 3 times or more), and the administration lasts for 2 days.
  • continuous administration for 3 days may refer to administration once a day (twice, 3 times or more), and continuous administration for 3 days.
  • continuous administration for 5 days may be administered once a day (twice, 3 times or more) for 5 consecutive days.
  • continuous administration for 7 days may refer to administration once a day (twice, 3 times or more), and continuous administration for 7 days.
  • the continuous administration period of 10 days may refer to the administration once a day (twice, three times or more), and the administration lasts for 10 days.
  • continuous administration for 14 days may refer to administration once a day (twice, three times or more) for 14 consecutive days.
  • continuous administration for more than 7 days may refer to administration once a day (twice, 3 times or more), and continuous administration for more than 7 days.
  • discontinuous administration generally refers to the repeated administration of the same drug of the same type within a dosing cycle instead of daily administration, which may also be referred to as intermittent and/or pulsed administration. Discontinuous administration can be regular or irregular. In the case of discontinuous administration, within the dosing cycle. For any continuous period of time, if the drug is administered every day and continues to be administered, it also belongs to the situation of continuous administration within this period of time.
  • the term "substantially does not affect” generally means that compared with the therapeutic effect of using the chemotherapy alone, the therapeutic effect of the combination of the drug described in the present application and the chemotherapy is equivalent, or does not cause significant disadvantages .
  • the degree of tumor volume reduction caused by the combination of the drug and the chemotherapy is the same, or the degree of reduction is not less than About 5%, not less than about 4%, not less than about 3%, not less than about 2%, not less than about 1%, not less than about 0.5%, not less than about 0.1%, not less than about 0.01%, not less than about 0.001 % or less.
  • gastrointestinal adverse event generally refers to a harmful, undesired, gastrointestinal-related A response, effect, action, effect, result or influence of or manifested in the gastrointestinal region. Also known as adverse gastrointestinal effects, adverse gastrointestinal effects, or adverse gastrointestinal consequences. Gastrointestinal adverse events include adverse events in various parts of the digestive system, such as the digestive tract and glands.
  • gastrointestinal adverse events may include, but are not limited to, abdominal distension, abdominal pain, anal fissure, anal fistula, anal bleeding, anal mucositis, anal necrosis, anal pain, anal stenosis, anal ulcer, ascites, hiccups, cecal bleeding, cheilitis , chylous ascites, colitis, colonic fistula, colonic hemorrhage, colonic obstruction, colonic perforation, colonic stenosis, colonic ulcer, constipation, dental caries, diarrhea, dry mouth, duodenal fistula, duodenal hemorrhage, duodenum Intestinal obstruction, duodenal perforation, duodenal stricture, duodenal ulcer, dyspepsia, dysphagia, enterocolitis, intestinal fistula, esophageal fistula, esophageal hemorrhage, esophageal necrosis
  • gastrointestinal side effect generally refers to the harmful and adverse effects caused by prophylactic or therapeutic drugs related to or manifested in the gastrointestinal tract area. Adverse effects are often undesired, but undesired effects are not necessarily adverse. Adverse effects of preventive or therapeutic medicines may be harmful, uncomfortable or dangerous. Gastrointestinal side effects include side effects of various parts of the digestive system such as the digestive tract and glands. Chemotherapy-related gastrointestinal side effects may refer to any abnormal clinical manifestations of the gastrointestinal tract that are temporally associated with the use of a chemotherapeutic agent, and which may not be causally related to the administration of the chemotherapeutic agent.
  • gastric mucosal injury disease generally refers to a disease or condition whose symptoms are gastric mucosal injury, and gastric mucosal injury may include abnormal color of gastric mucosa, bleeding points, congestion and erosion.
  • intestinal mucosal injury disease generally refers to a disease or condition whose symptoms are intestinal mucosal injury, and intestinal mucosal injury may include abnormal color of intestinal mucosa, bleeding points, congestion and erosion.
  • diarrhea generally refers to a disease or condition characterized by increased frequency of bowel movements and/or loose or watery bowel movements.
  • said diarrhea may appear or worsen after said administration of chemotherapy.
  • descriptions of standardized definitions for diarrhea can be found in versions of the Common Terminology Criteria for Adverse Events (CTCAE) published by the National Cancer Institute (NCI).
  • grade of diarrhea in animal experiments: such as the Akinobu Kurita method (Cancer Chemother Pharmacol 2000; 46:211-20.) to grade the severity of diarrhea, where grade 0: normal stool; grade 1: Mild diarrhea with slightly wet and soft stools; Grade 2: moderate diarrhea with loose stools and mild perianal staining; Grade 3: severe diarrhea with watery stools and severe perianal coloring.
  • constipation generally refers to a disease or condition characterized by irregular, infrequent or difficult bowel movements. In the present application, said constipation may occur or worsen after said administration of chemotherapy.
  • CCAE Common Terminology Criteria for Adverse Events
  • NCI National Cancer Institute
  • enteritis generally refers to inflammation of the intestine. It includes colitis, enteritis, enterocolitis, duodenitis, ileitis, appenditis, proctitis and/or jejunitis. In the present application, said enteritis may appear or worsen after said administration of chemotherapy.
  • CCAE Common Terminology Criteria for Adverse Events
  • NCI National Cancer Institute
  • the term "without prevention or treatment” generally refers to the situation where prevention or treatment of gastrointestinal adverse events is not implemented, and measures are not taken to weaken or eliminate gastrointestinal adverse events.
  • Measures to reduce or eliminate gastrointestinal adverse events may be, for example, administering drugs or other means to prevent or treat gastrointestinal adverse events, stopping administration of drugs or other means that cause gastrointestinal adverse events, said measures include The compound represented by the formula I of the present application or the drug is administered.
  • the adverse events of the gastrointestinal tract will occur after 1 hour, 2 hours, or 3 hours after the administration of the chemotherapy.
  • NCI-CTCAE generally refers to the standardized definition of adverse events published by the National Cancer Institute (NCI) - the Common Terminology Criteria for Adverse Events (CTCAE) to describe severe organ toxicity in cancer treatment patients degree. The standard can be continuously updated as the scientific basis advances.
  • NCI-CTCAE may include any version of "NCI-CTCAE”.
  • constipation and diarrhea are defined as 5 grades, as shown in Table 1 and Table 2.
  • CTCAE level standard Level 1 Episodic or intermittent symptoms; occasional use of stool softeners, laxatives, dietary modification, or enemas level 2 Persistent symptoms with long-term use of laxatives or enemas; limit instrumental ADL level 3 Constipation with manual evacuation instructions; limiting self-care Level 4 Life-threatening consequences; indicates urgent intervention level 5 die
  • cancer generally refers to any medical condition mediated by the growth, proliferation or metastasis of tumor or malignant cells and giving rise to solid tumors and non-solid tumors (eg, leukemia).
  • Cancers described in this application may include, but are not limited to, epithelial malignancies (cancers of epithelial origin), lung cancer (e.g., non-small cell lung cancer), breast cancer, skin cancer, bladder cancer, colon cancer, bowel ( GI) cancer, prostate cancer, pancreatic cancer, uterine cancer, cervical cancer, ovarian cancer, esophageal cancer, head and neck cancer, stomach cancer and laryngeal cancer.
  • the present application provides a use of a compound represented by formula I in the preparation of a medicament, which can be used to prevent, relieve and/or treat chemotherapy-related gastrointestinal side effects in a subject:
  • Z is -(CH2) X -, wherein X is 1, 2, 3 or 4, or -O-(CH2) Z -, wherein z is 2, 3 or 4;
  • X and X' are each independently CH or N;
  • R, R 8 and R 11 are each independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S, - (Alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclyl, -(alkylene) m -heteroaryl , -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)-NR 3 R 4 , -(alkylene) m -OR 5 , -(alkylene) m -S(O)nR 5 , or -(alkylene) m -S(O) n -NR 3 R 4 , either of which can optionally be independently modified by one or more R The group is substituted, and
  • R is independently aryl, alkyl, cycloalkyl, or haloalkyl, wherein each of said alkyl, cycloalkyl, and haloalkyl optionally includes O or N in the chain instead of carbon heteroatom and two R on adjacent ring atoms or on the same ring atom, together with the ring atom to which they are attached, optionally form a 3-8 membered ring;
  • y is 0, 1, 2, 3 or 4;
  • R 2 is -(alkylene) m -heterocyclyl, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C( O)-NR 3 R 4 , -(alkylene) m -C(O)-O-alkyl; -(alkylene) m -OR 5 , -(alkylene) m -S(O) n -R or - (alkylene) m -S(O) n - NR3R4 , either of which may be optionally independently substituted with one or more Rx groups as valence permits, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring, and wherein m is 0 or 1 and n is 0, 1 or 2;
  • R 3 and R 4 are independently:
  • Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which are allowed by the valence may be optionally independently substituted with one or more R groups, and wherein two R groups bound to the same or adjacent atoms may optionally combine to form a ring ; or R and R Together with the nitrogen atoms to which they are attached, may combine to form a heterocyclic ring optionally independently substituted with one or more Rx groups as valency permits, and wherein two Rx groups bonded to the same or adjacent atoms may be optionally combined to form a ring;
  • alkyl alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl or heteroarylalkyl, wherein Either may be optionally substituted independently with one or more R groups as valency permits;
  • R x is independently halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, Heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene -OR 5 , -(alkylene) m -S(O) n -R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)-R 5 , -(alkylene) m -C(S)-R 5 , -(alkylene) m -C(O)-OR
  • alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkyl groups may be further independently substituted by one or more of the following groups:
  • n 0, 1 or 2
  • m 0 or 1
  • R3 * and R4 * are independently:
  • alkyl alkenyl, alkynylcycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl or heteroarylalkyl, any of which One may be optionally substituted independently with one or more R x groups as valence permits; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may be combined to form optionally are heterocycles independently substituted with one or more R x groups; and
  • R 6 is H or lower alkyl, -(alkylene) m -heterocyclyl, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene - ( alkylene) m -OR 5 , -(alkylene) m -S(O) n -R 5 or - ( alkylene) m - S(O) n -NR 3 R 4 , any of which may be optionally substituted independently by one or more R x groups as valence permits, and two of which are bound to the same or adjacent atoms R x groups can optionally combine to form a ring;
  • the present application provides a method for preventing, alleviating and/or treating chemotherapy-related gastrointestinal side effects in a subject, the method comprising administering the compound represented by the formula I.
  • the term "compound represented by formula I” may be referred to as "compound of formula I", “formula I”. Such terms are also defined to include all forms of the compounds of formula I, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs and metabolites.
  • compounds of formula I, or pharmaceutically acceptable salts thereof can exist in unsolvated as well as solvated forms.
  • the binding force of solvent or water is strong, the complex has a well-defined stoichiometry, which is not affected by humidity.
  • the solvent or water is weakly bound, such as in channel solvates and hygroscopic compounds, the water/solvent content will depend on humidity and drying conditions, in which case non-stoichiometry is the norm.
  • Compounds of formula I may have asymmetric carbon atoms.
  • the carbon-carbon bonds of the compounds of formula I may be represented by solid lines, solid wedges or dotted wedges.
  • the use of a solid line to delineate a bond to an asymmetric carbon atom is meant to include all possible stereoisomers at that carbon atom (eg, specific enantiomers, racemic mixtures, etc.).
  • Compounds of the present application may contain more than one asymmetric carbon atom. In these compounds, the use of solid lines to indicate linkages to asymmetric carbon atoms is intended to indicate that all possible stereoisomers are to be included.
  • the compounds of formula I can exist as enantiomers and diastereomers or as racemates and mixtures. Indicates that the use of solid lines to depict bonds to one or more asymmetric carbon atoms in a compound of formula I, and the use of solid or dashed wedges to depict bonds to other asymmetric carbon atoms in the same compound indicates the presence of a mixture of diastereoisomers.
  • the compounds of the present application may exist in the form of clathrates or other complexes.
  • Complexes such as clathrates, drug-host inclusion complexes, in which, in contrast to the above-mentioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric amounts may be included within the scope of the present application.
  • complexes of formula I which contain two or more organic and/or inorganic components which may be stoichiometric or non-stoichiometric.
  • the resulting complex can be ionized, partially ionized or not ionized.
  • Stereoisomers of Formula I include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotamers, conformations Isomers and tautomers, compounds of formula I, include compounds exhibiting more than one type of isomerism; and mixtures thereof (eg, racemates and diastereomeric pairs). Also included are acid or base addition salts in which the counterion is optically active, such as D-lactate or L-lysine, or the racemates, such as DL-tartrate or DL-arginine.
  • the first category is the aforementioned racemic compounds (true racemates) in which a homogeneous form of crystals is produced containing both enantiomers in equimolar amounts.
  • the second type is a racemic mixture or agglomerate in which two forms of crystals are produced in equimolar amounts, each form containing a single enantiomer.
  • Compounds of formula I may exhibit tautomerism and structural isomerism.
  • compounds of formula I may exist in several tautomeric forms, including enol and imine forms, and keto and enamine forms, as well as geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of formula I.
  • Tautomers exist in solution as a mixture of tautomers. In solid form, usually one tautomer predominates. Even if one tautomer can be described, the present invention includes all tautomers of the compounds of formula I.
  • the present application may also include isotopically labeled compounds which are identical to those described in Formula I, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from that found in nature.
  • Isotopes that can be added to the compound of formula I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • isotopically labeled compounds of formula I for example to which radioactive isotopes (eg 3 H and 14 C) have been added, are useful in drug and/or substrate tissue distribution assays due to their ease of preparation and detectability. Heavier isotopes, such as2H , may afford certain therapeutic advantages due to their greater metabolic stability, eg, increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of formula I can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of the present application may be used in the form of salts derived from inorganic or organic acids. Certain compounds have advantages such as enhanced drug stability at different temperatures and humidity, or desirable solubility in water/oil due to the physical properties of one or more salts. In some cases, salts of compounds can also be used as aids in the isolation, purification and/or elucidation of compounds.
  • the compound has the structure of formula I and R 6 may not exist.
  • R x in the formula I may not be further substituted.
  • the R 8 in the formula I may be hydrogen or C 1 -C 3 alkyl.
  • the R 11 in the formula I may be hydrogen or C 1 -C 3 alkyl.
  • the compound may comprise a compound shown in formula Ia:
  • the X in the formula I or formula Ia may be C.
  • the X' in the formula I or formula Ia may be N.
  • the R in the formula I or formula Ia can be hydrogen or C 1 -C 3 alkyl.
  • the R 2 in the formula I or formula Ia may be -(alkylene) m -heterocyclyl, -(alkylene) m -NR 3 R 4 , -(alkylene ) m -C(O)-NR 3 R 4 , -(alkylene) m -C(O)-O-alkyl or -(alkylene) m -OR 5 , any of which is allowed by the valence may be optionally independently substituted with one or more R x groups, and wherein two R x groups bonded to the same or adjacent atoms may optionally combine to form a ring, and wherein m is 0 or 1 .
  • the R 2 in the formula I or formula Ia may be -(alkylene) m -heterocyclyl, -(alkylene) m -NR 3 R 4 , -(alkylene ) m -C(O)-NR 3 R 4 , -(alkylene) m -C(O)-O-alkyl or -(alkylene) m -OR 5 , without further substitution.
  • m in the R 2 in the formula I or formula Ia can be 1.
  • the alkylene group in the R 2 in the formula I or formula Ia may be a methylene group.
  • R2 * can be bond, alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m -and -(alkylene) m -NH-(alkylene) m -, wherein each m can be independently 0 or 1;
  • P can be a 4-8 membered monocyclic or bicyclic saturated heterocyclic group
  • Each R x1 can independently be -(alkylene) m -(C(O)) m -(alkylene) m -(N(R N )) m -(alkyl) m , wherein each m may independently be 0 or 1, provided that at least one m may be 1; -(C(O))-O-alkyl; -(alkylene) m -cycloalkyl, where m may be 0 or 1 -N(R N )-cycloalkyl; -C(O)-cycloalkyl; -(alkylene) m -heterocyclyl, wherein m can be 0 or 1; or -N(R N )- Heterocyclyl; -C(O)-heterocyclyl; -S(O) 2 -(alkylene) m , where m can be 1 or 2, where:
  • RN can be H, C 1 to C 4 alkyl, or C 1 to C 6 heteroalkyl, and
  • R x1 may form a ring together with the atoms to which they are attached on P which may be the same atom;
  • t 0, 1 or 2.
  • each R x1 in R 2 may be optionally unsubstituted alkyl, halogen or hydroxy substitution.
  • R x1 in R 2 may be hydrogen or unsubstituted C 1 -C 4 alkyl.
  • At least one R x1 of the R 2 may be -(alkylene) m -heterocyclyl, wherein m is 0 or 1.
  • R in the formula I or formula Ia is Wherein P* can be a 4-8 membered monocyclic or bicyclic saturated heterocyclic group.
  • R2 * is a bond, alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m - , -(alkylene) m -S(O) 2 -(alkylene) m -and -(alkylene) m -NH-(alkylene) m -, wherein each m is independently 0 or 1, s is 0, 1 or 2;
  • P is 4 to 8 membered monocyclic or bicyclic and heterocyclic groups
  • P1 is a 4 to 6 membered monocyclic saturated heterocyclyl
  • each R X2 can be independently hydrogen or alkyl; and s is 0, 1 or 2.
  • P1 in the R 2 may include at least one nitrogen.
  • any alkylene group in R 2* in any of the above embodiments may not be further substituted.
  • the R 2 * in the R 2 may be a bond.
  • the R x1 in the R 2 may be hydrogen, methyl or propyl.
  • the R2 can be any suitable R2
  • the compound shown in the formula I can be selected from the following group:
  • the compound shown in the formula I can be
  • the compound shown in the formula I can be hydrochloride form.
  • the compound shown in the formula I can be
  • the compound shown in the formula I can be hydrochloride form.
  • the compound shown in the formula I can be
  • the compound shown in the formula I can be hydrochloride form.
  • the compound shown in the formula I can be
  • the compound shown in the formula I can be hydrochloride form.
  • the chemotherapeutic agent used in the chemotherapy can be selected from any compound or agent used for cancer prevention, alleviation and/or treatment in the categories known to those skilled in the art.
  • chemotherapy may include DNA synthesis inhibitors, RNA synthesis inhibitors, protein synthesis inhibitors, cell division inhibitors, DNA base analogs, topoisomerase inhibitors and/or telomerase synthesis inhibitors.
  • chemotherapeutic agents may be toxic to immune effector cells.
  • chemotherapeutic agents can inhibit cell growth.
  • the chemotherapeutic agent administered may be a DNA damaging chemotherapeutic agent.
  • chemotherapeutic agents are protein synthesis inhibitors, DNA-damaging chemotherapeutic agents, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binders, thiolate alkylating agents, guanine alkylating agents Tubulin-binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazophosphorine compounds, integrin inhibitors such as cilengitide, camptothecin, or homocamptothecin , antifolates, folate antimetabolites, telomerase inhibitors and/or telomere DNA binding compounds.
  • the alkylating agents may include alkyl sulfonates such as busulfan, improsulfan, and pipoxulfan; aziridines such as benzodizepa, carboquinone, meturedepa, and uridine; Alternate; ethyleneimines and methylmelamines such as hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as phenylbutyric acid Nitrogen mustard, naphthalene nitrogen mustard, cyclophosphamide, estramustine, dichloromethyldiethylamine, methoxymustine hydrochloride, melphalan, new nitrogen mustard (novembichine), phenesterine, prednimustine, koji lofosfamide and uracil mustard; and nitrosoureas such as carmustine, chlorurecin, formustine, lomustine, nimustine,
  • chemotherapeutic agents may include daunorubicin, doxorubicin, idarubicin, epirubicin, mitomycin, and streptozotocin.
  • Chemotherapeutic antimetabolites may include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), floxuridine, cytarabine, pentostatin, methotrexate , azathioprine, acyclovir, adenine ⁇ -1-D-arabinoside, methotrexate, aminopterin, 2-aminopurine, aphidicolin, 8-azaguanine, diazo Serine, 6-azauracil, 2'-azido-2'-deoxynucleoside, 5-bromodeoxycytidine, cytosine ⁇ -1-D-arabinoside, diazooxynorleucine, dideoxy nucleosides, 5-
  • protein synthesis inhibitors may include abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, idamicin A, emetine, erythromycin, Ethionine, Fluoride, 5-Fluorotryptophan, Fusidic Acid, Guanylmethylene Diphosphonate and Guanylimidyl Diphosphonate, Kanamycin, Kasugamycin, Yellow Mycin and O-methylthreonine.
  • protein synthesis inhibitors include modeccin, neomycin, norvaline, micycline, paromomycine, puromycin, ricin, shiga toxin, pyrooxytetracycline, sparsomycin, spectinomycin, streptomycin tetracyclines, thiostreptons, and trimethoprim.
  • DNA synthesis inhibitors may include alkylating agents such as dimethyl sulfate, nitrogen and sulfur mustards; intercalating agents such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, diiodide Propidium-interleaving; topoisomerase inhibitors such as irinotecan, teniposide, coumarin, nalidixic acid, novobiocin, and oxolinic acid; cell division inhibitors including colcemid, mitol Anthraquinones, colchicine, vinblastine, and vincristine; and other agents such as distamycin and netlastine.
  • alkylating agents such as dimethyl sulfate, nitrogen and sulfur mustards
  • intercalating agents such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, diiodide Propidium-interleaving
  • the chemotherapeutic agent may be a DNA complex binding agent such as camptothecin or etoposide; a thiolate alkylating agent such as nitrosourea, BCNU, CCNU, ACNU or fotesmustine; a guanine alkylating agent, Examples include temozolomide, tubulin-binding agents such as vinblastine, vincristine, vinorelbine, vinflunine, nodocin 52, halichondrin such as halichondrin B, dolastatin such as dolastatin 10, and dolastatin Toxin 15, hemiasterlins (eg, hemiasterlin A and hemiasterlin B), colchicine, combrestatins, 2-methoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, asculonide; DNA polymerization Enzyme inhibitors such as cytarabine; anticancer enzymes such as as as
  • the compound represented by the formula I can be used to prevent, relieve and/or treat one or more chemotherapy-related gastrointestinal side effects mentioned above.
  • the compound represented by the formula I can be used to prevent, relieve and/or treat gastrointestinal side effects associated with the administration of the following chemotherapeutic agents: fluorouracil, oxaliplatin (Oxaliplatin), irinotecan, topotecan Kang, etoposide, cisplatin, docetaxel, gemcitabine, carboplatin, methotrexate, doxorubicin, cytarabine, vinorelbine and capecitabine, and combinations of the above.
  • fluorouracil oxaliplatin
  • irinotecan topotecan Kang
  • etoposide cisplatin
  • docetaxel gemcitabine
  • carboplatin methotrexate
  • doxorubicin doxorubicin
  • cytarabine vinorelbine
  • capecitabine capecitabine
  • the compound represented by the formula I can be used to prevent, relieve and/or treat gastrointestinal side effects associated with the administration of the following chemotherapeutic agents: fluorouracil, oxaliplatin, irinotecan (CPT-11), four Hydrofolate, and their combinations.
  • the compound represented by formula I can be used to prevent, alleviate and/or treat the following chemotherapy-related gastrointestinal side effects: 5-fluorouracil, irinotecan and oxaliplatin, and their combinations.
  • the chemotherapeutic agents may not include tumor targeting drugs.
  • the chemotherapeutic agent may not include those kinase inhibitors that inhibit abnormally activated kinases to prevent the division of cancer cells.
  • the chemotherapeutic agents may not include antibodies and/or angiogenesis inhibitors.
  • the chemotherapeutic agent may not include a tyrosine kinase inhibitor.
  • the chemotherapeutic agent may be administered continuously.
  • the chemotherapy can be administered for 2, 3, 4, 5, 6, 7, 8, 9 or more consecutive days.
  • the chemotherapy is administered continuously for no more than 7 days, for example, the chemotherapy can be administered for 2 days, 3 days, 4 days, 5 days, 6 days or 7 days in a row.
  • the administration frequency of the chemotherapy can be once a day, twice a day, three times a day or others.
  • the chemotherapeutic agent may be administered discontinuously.
  • the administration frequency of the chemotherapy is once every two days, once every three days, twice every three days or other.
  • the duration of continuous administration of the chemotherapy may not exceed 7 days.
  • the chemotherapy may be administered for less than 7 consecutive days (eg, 2, 3, 4, 5, or 6 consecutive days).
  • the administration cycle of the chemotherapy can be 3 days, 5 days, 7 days, 2 weeks, 20 days, 1 month, 2 months or longer.
  • administration route and/or administration time of the chemotherapeutic agent please refer to the drug instruction of the chemotherapeutic agent.
  • the compound of formula I may be used in combination with one or more other cancer treatments.
  • the other cancer therapy may be a method conventionally used in the art to treat cancer, such as a cytotoxic anticancer agent, an immunotherapeutic anticancer agent or a hormonal therapy anticancer agent.
  • drugs for cancer treatment may also be used in combination with radiation therapy or surgery.
  • when the compound represented by formula I and other anticancer agents are used in combination they may be administered to the subject at the same time, or administered separately at certain intervals.
  • the compound represented by formula I can prevent, relieve and/or treat gastrointestinal side effects associated with administration of chemotherapy in subjects.
  • chemotherapy-related gastrointestinal side effects may refer to the gastrointestinal side effects caused by the administration of the chemotherapy, and the gastrointestinal side effects are generated or aggravated after the administration of the chemotherapy.
  • the gastrointestinal side effects can occur after about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, About 7 hours later, about 8 hours later, about 9 hours later, about 10 hours later, about 11 hours later, about 12 hours later, about 1 day later, about 2 days later, about 4 days later, about 7 days later, about 2 weeks later , appeared or aggravated after about 3 weeks, about 1 month, about 2 months or more.
  • the subject prior to administering the chemotherapy to the subject, the subject does not experience the gastrointestinal side effects; after administering the chemotherapy to the subject, the subject develops the described gastrointestinal side effects.
  • the subject prior to administering the chemotherapy to the subject, the subject has developed the gastrointestinal side effect; after administering the chemotherapy to the subject, all of the subject's The severity of the above-mentioned gastrointestinal side effects was aggravated.
  • the gastrointestinal side effects for example, diarrhea, enteritis or constipation
  • the gastrointestinal side effects can be increased by at least about 10%, for example, by about 15%, about 20%, about 25% , about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or higher.
  • the degree of the gastrointestinal side effect for example, diarrhea, enteritis or constipation
  • the degree of the gastrointestinal side effect is increased from grade 1 to grade 2 level, from level 1 to level 3, from level 1 to level 4, from level 1 to level 5, from level 2 to level 3, from level 2 to level 4 level, from level 2 to level 5, from level 3 to level 4, from level 3 to level 5, or from level 4 to level 5.
  • the subject's constipation score is raised from grade 0 to grade 1, from grade 0 to grade 2, from grade 0 Move up to level 3, level 1 to level 2, level 1 to level 3 or level 2 to level 3.
  • the gastrointestinal side effects include gastric mucosal injury diseases and/or intestinal mucosal injury diseases.
  • the gastrointestinal side effects include diarrhea, abdominal pain, nausea, vomiting, mucositis, loss of appetite, gastric ulcer, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulceration and/or intestinal necrosis.
  • the gastrointestinal side effects include abnormal excretion.
  • the gastrointestinal side effects include diarrhea and/or constipation.
  • the chemotherapy-related gastrointestinal side effects include chemotherapy-related gastric mucosal injury diseases and/or chemotherapy-related intestinal mucosal injury diseases.
  • the gastrointestinal side effects associated with chemotherapy include diarrhea associated with chemotherapy, abdominal pain associated with chemotherapy, nausea associated with chemotherapy, vomiting associated with chemotherapy, mucositis associated with chemotherapy, and Chemotherapy-related anorexia, chemotherapy-related gastric ulcer, chemotherapy-related gastritis, chemotherapy-related constipation, chemotherapy-related enteritis, chemotherapy-related intestinal perforation, chemotherapy-related intestinal bleeding, chemotherapy-related ulcer and/or bowel necrosis associated with chemotherapy.
  • the chemotherapy-related gastrointestinal side effects include chemotherapy-related excretion abnormalities.
  • the chemotherapy-related gastrointestinal side effects include chemotherapy-related diarrhea and/or chemotherapy-related constipation.
  • the severity of chemotherapy-related gastrointestinal side effects of the subject is alleviated.
  • the alleviation may generally mean that the onset or development of gastrointestinal side effects in the subject is delayed.
  • the symptoms of gastrointestinal side effects of the subject can be alleviated.
  • the subject's gastrointestinal side effects can be alleviated by at least about 10%, for example, about 15%, about 20%, about 25%, about 30%. , about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or more relief.
  • the symptoms of gastrointestinal side effects for example, diarrhea, enteritis and/or constipation
  • the symptoms of gastrointestinal side effects can be reduced from grade 5 to grade 4, From level 5 to level 3, from level 5 to level 2, from level 5 to level 1, from level 4 to level 3, from level 4 to level 2, Downgrade from level 4 to level 1, level 3 to level 2, level 3 to level 1 or level 2 to level 1.
  • the subject's diarrhea score can be reduced from grade 3 to grade 2, from grade 3 to grade 1, from grade 3 to grade Level 0, downgrade from level 2 to level 1, downgrade from level 2 to level 0, or downgrade from level 1 to level 0.
  • prevention generally refers to preventing the onset, recurrence or spread of a disease or one or more symptoms thereof. "Prevention” may be used interchangeably with “prophylactic treatment” in this application.
  • prophylaxis generally refers to providing, prior to the onset of symptoms, with or without other agents described herein, to a patient suffering from a disease or condition described herein. treatment with the above-mentioned drugs.
  • patients with a family history of a particular disease may be candidates for prophylactic regimens.
  • patients with a history of recurrent symptoms are also potential candidates for prophylaxis.
  • treating generally refers to eliminating or ameliorating a disease, or one or more symptoms associated with a disease.
  • treatment generally refers to the elimination or remission of a disease by administering one or more therapeutic agents to a patient suffering from the disease.
  • treatment may be the administration of a drug in the presence or absence of other therapeutic agents after the onset of symptoms of a particular disease.
  • subject used in this application generally refers to humans or non-human animals (including mammals) that require diagnosis, prognosis, improvement, prevention, mitigation and/or treatment of diseases, especially compounds shown in formula I Those subjects of treatment, mitigation or prevention.
  • the subject can include a cancer patient.
  • the cancer patient may have been, is and/or will be administered chemotherapy.
  • the subject can be a human or a non-human mammal.
  • Non-human mammals can include any mammalian species other than humans, such as livestock animals (e.g., cows, pigs, sheep, chickens, rabbits, or horses), or rodents (e.g., rats and mice), or Primates (eg, gorillas and monkeys), or domestic animals (eg, dogs and cats).
  • livestock animals e.g., cows, pigs, sheep, chickens, rabbits, or horses
  • rodents e.g., rats and mice
  • Primates eg, gorillas and monkeys
  • domestic animals eg, dogs and cats.
  • an effective amount used in the present application generally refers to the amount of the drug that can alleviate or eliminate the disease or symptom of the subject, or can prophylactically inhibit or prevent the occurrence of the disease or symptom.
  • An effective amount may be that amount of a drug that alleviates to a certain extent one or more diseases or symptoms in a subject; may partially or completely restore one or more physiological or biochemical parameters related to the cause of the disease or symptoms to the normal amount of the drug; and/or the amount of the drug that can reduce the likelihood of the disease or symptoms occurring.
  • the drug or the compound represented by formula I can be administered to prevent, relieve and/or treat the occurrence or aggravation of gastrointestinal side effects.
  • administering the drug or the compound represented by formula I 0.5-12 hours before administering chemotherapy can prevent, relieve and/or treat the occurrence or aggravation of gastrointestinal side effects.
  • the site of administration of the compound represented by formula I may or may not be the site of occurrence of cancer or the site of potential metastasis of cancer.
  • the administered moiety may or may not be the primary site of cancer.
  • the administration part may or may not be a metastatic site of cancer.
  • the site of metastasis may include the site of cancer metastasis caused by lymphatic metastasis, vascular metastasis and/or implantation metastasis.
  • the metastatic site may include bone, brain, liver, stomach and/or lung.
  • the administered moiety may or may not be a recurrence site of the cancer.
  • the compound represented by formula I described in the present application can be administered by administration methods known in the art, such as injection administration (for example, subcutaneous, intraperitoneal, intra-articular, intraarterial, intrathecal, intrasternal, intrathecal, Intralesional, intracranial, intramuscular, intradermal, and intravenous bolus or infusion) or non-injection administration (eg, oral, nasal, sublingual, vaginal, rectal, or topical administration).
  • injection administration for example, subcutaneous, intraperitoneal, intra-articular, intraarterial, intrathecal, intrasternal, intrathecal, Intralesional, intracranial, intramuscular, intradermal, and intravenous bolus or infusion
  • non-injection administration eg, oral, nasal, sublingual, vaginal, rectal, or topical administration.
  • the compound represented by formula I of the present application can be administered in the form of pharmaceutical combination or kit.
  • the compound represented by formula I described in this application can be administered by the same administration route as
  • the drug and/or the compound represented by formula I can be prepared for oral administration.
  • the drug and/or the compound represented by formula I can be prepared as powder, tablet, granule, capsule, solution, emulsion and/or suspension.
  • the drug and/or the compound represented by formula I may be prepared for administration by injection, such as subcutaneous injection, intramuscular injection, intraperitoneal injection and/or intravenous injection.
  • injection such as subcutaneous injection, intramuscular injection, intraperitoneal injection and/or intravenous injection.
  • the drug and/or the compound represented by formula I can be prepared as an injection.
  • the dosage of the compound represented by formula I may be about 0.01-1000 mg/kg, for example, about 0.01-800 mg/kg, about 0.01-900 mg/kg, about 0.01-800 mg/kg, about 0.01-700mg/kg, about 0.01-600mg/kg, about 0.01-500mg/kg, about 0.01-400mg/kg, about 0.01-300mg/kg, about 0.01-200mg/kg, about 0.01-100mg/kg, about 0.1 -1000mg/kg, about 1-1000mg/kg, about 10-1000mg/kg, about 50-1000mg/kg, about 100-1000mg/kg, about 0.1-800mg/kg, about 1-600mg/kg, about 10- 500 mg/kg, about 10-400 mg/kg, about 15-300 mg/kg, about 50-250 mg/kg, or about 50-200 mg/kg.
  • the dosage of the compound represented by the formula I may be about 0.01-1000 mg/kg when administered orally, for example, about 0.01-800 mg/kg, about 0.01-900 mg/kg, about 0.01-800 mg /kg, about 0.01-700mg/kg, about 0.01-600mg/kg, about 0.01-500mg/kg, about 0.01-400mg/kg, about 0.01-300mg/kg, about 0.01-200mg/kg, about 0.01-100mg/kg kg, about 0.1-1000mg/kg, about 1-1000mg/kg, about 10-1000mg/kg, about 50-1000mg/kg, about 100-1000mg/kg, about 0.1-800mg/kg, about 1-600mg/kg , about 10-500 mg/kg, about 10-400 mg/kg, about 15-300 mg/kg, about 50-250 mg/kg, or about 50-200 mg/kg.
  • the dosage of the compound represented by the formula I can be about 0.01-1000 mg/kg when administered by injection, for example, about 0.01-800 mg/kg, about 0.01-900 mg/kg, about 0.01-800 mg /kg, about 0.01-700mg/kg, about 0.01-600mg/kg, about 0.01-500mg/kg, about 0.01-400mg/kg, about 0.01-300mg/kg, about 0.01-200mg/kg, about 0.01-100mg/kg kg, about 0.1-1000mg/kg, about 1-1000mg/kg, about 10-1000mg/kg, about 50-1000mg/kg, about 100-1000mg/kg, about 0.1-800mg/kg, about 1-600mg/kg , about 10-500 mg/kg, about 10-400 mg/kg, about 15-300 mg/kg, about 50-250 mg/kg, or about 50-200 mg/kg.
  • the compound represented by the formula I can be administered 0.5-24 hours before the administration of the chemotherapeutic agent, and can be administered orally, and the dosage can be about 50-150 mg/kg, and the administration frequency can be 1 week. Once to once every 2 weeks (eg, once 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days).
  • the compound represented by the formula I can be administered 0.5-12 hours before the administration of the chemotherapeutic agent, and can be administered orally, and the dosage can be about 50-150 mg/kg, and the administration cycle can be 1 week. Once to once every 2 weeks (eg, once 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days).
  • the compound represented by the formula I can be administered by injection 0.5-24 hours before the administration of the chemotherapeutic agent, and the dosage can be about 50-150 mg/kg, and the administration frequency can be 1 week. Once to once every 2 weeks (eg, once 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days).
  • the compound represented by the formula I can be administered 0.5-12 hours before the administration of the chemotherapeutic agent, and can be administered by injection, and the dosage can be about 50-150 mg/kg, and the administration cycle can be 1 week. Once to once every 2 weeks (eg, once 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days).
  • compound I and its pharmaceutically acceptable salt can prevent, relieve and/or treat fluorouracil-related gastrointestinal side effects in a subject.
  • the compound I and a pharmaceutically acceptable salt thereof can be administered 0.5-24 hours before the administration of the fluorouracil, and the compound I and a pharmaceutically acceptable salt thereof can be administered by injection or oral administration, the The dosage of compound I and its pharmaceutically acceptable salts can be about 100 mg/kg-about 150 mg/kg.
  • the compound I and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of the fluorouracil, and the compound I and a pharmaceutically acceptable salt thereof can be administered by intravenous injection.
  • the dosage of the compound I and the pharmaceutically acceptable salt thereof can be about 100 mg/kg-about 150 mg/kg.
  • the compound I and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of the fluorouracil, and the compound I and a pharmaceutically acceptable salt thereof can be administered by intraperitoneal injection
  • the dosage of the compound I and the pharmaceutically acceptable salt thereof can be about 100 mg/kg-about 150 mg/kg.
  • the compound I and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of the fluorouracil, and the compound I and a pharmaceutically acceptable salt thereof can be intramuscularly injected
  • the dosage of the compound I and the pharmaceutically acceptable salt thereof can be about 100 mg/kg-about 150 mg/kg.
  • the compound I and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of the fluorouracil, and the compound I and a pharmaceutically acceptable salt thereof can be administered orally , the dosage of the compound I and the pharmaceutically acceptable salt thereof may be about 100 mg/kg-about 150 mg/kg.
  • Compound I and its pharmaceutically acceptable salt can prevent, relieve and/or treat oxaliplatin-related gastrointestinal side effects in a subject.
  • the compound I and a pharmaceutically acceptable salt thereof can be administered 0.5-24 hours before the administration of the oxaliplatin, and the compound I and a pharmaceutically acceptable salt thereof can be administered by injection or oral administration , the dosage of the compound I and the pharmaceutically acceptable salt thereof may be about 100 mg/kg-about 150 mg/kg.
  • the compound I and a pharmaceutically acceptable salt thereof can be administered 0.5-12h before the administration of the oxaliplatin, and the compound I and a pharmaceutically acceptable salt thereof can be
  • injection administration for example, intravenous injection or intraperitoneal injection
  • the dosage of the compound I and its pharmaceutically acceptable salts can be about 100 mg/kg-about 150 mg/kg.
  • compound I and its pharmaceutically acceptable salt can prevent, relieve and/or treat irinotecan-related gastrointestinal side effects in subjects.
  • the compound I and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of irinotecan, and the compound I and a pharmaceutically acceptable salt thereof can be administered by injection or oral administration,
  • the dosage of the compound I and the pharmaceutically acceptable salt thereof can be about 100 mg/kg-about 150 mg/kg.
  • compound I and its pharmaceutically acceptable salt can prevent, alleviate and/or treat gastrointestinal side effects associated with the combination of fluorouracil and irinotecan in subjects.
  • the compound I and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of the fluorouracil and irinotecan, and the compound I and a pharmaceutically acceptable salt thereof can be administered by injection or oral administration.
  • the dosage of the compound I and the pharmaceutically acceptable salt thereof can be about 100 mg/kg-about 150 mg/kg.
  • Compound I and its pharmaceutically acceptable salt can prevent, relieve and/or treat the combination of fluorouracil, oxaliplatin, irinotecan and tetrahydrofolate in subjects. associated gastrointestinal side effects.
  • the compound I and its pharmaceutically acceptable salts can be administered 0.5-12 hours before the administration of the fluorouracil, oxaliplatin, irinotecan and tetrahydrofolate, and the compound I and its pharmaceutically acceptable salts
  • the salt can be administered by injection or orally, and the dosage of the compound I and its pharmaceutically acceptable salt can be about 100 mg/kg-about 150 mg/kg.
  • compound I and its pharmaceutically acceptable salts can prevent, relieve and/or treat gastrointestinal side effects associated with gemcitabine in subjects.
  • compound I and its pharmaceutically acceptable salts can prevent, alleviate and/or treat gastrointestinal side effects associated with the combination of gemcitabine and carboplatin in subjects.
  • compound IV and pharmaceutically acceptable salts thereof can prevent, relieve and/or treat irinotecan-related gastrointestinal side effects in subjects.
  • the compound IV and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of irinotecan, the compound IV and a pharmaceutically acceptable salt thereof can be administered by injection, and the compound I and pharmaceutically acceptable salts thereof may be administered at a dose of about 100 mg/kg to about 150 mg/kg.
  • compound IV and its pharmaceutically acceptable salt can prevent, alleviate and/or treat fluorouracil-related gastrointestinal side effects in a subject.
  • the compound IV and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of the fluorouracil, and the compound IV and a pharmaceutically acceptable salt thereof can be administered by injection or oral administration, the The dosage of compound IV and its pharmaceutically acceptable salts can be about 100 mg/kg to about 150 mg/kg.
  • compound IV and its pharmaceutically acceptable salt can prevent, relieve and/or treat gastrointestinal side effects associated with the combination of fluorouracil and irinotecan in a subject.
  • the compound IV and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of the fluorouracil and irinotecan, and the compound IV and a pharmaceutically acceptable salt thereof can be administered by injection or oral administration.
  • the dosage of the compound IV and the pharmaceutically acceptable salt thereof can be about 100 mg/kg-about 150 mg/kg.
  • compound IV and its pharmaceutically acceptable salt can prevent, alleviate and/or treat the combination of fluorouracil, oxaliplatin, irinotecan and tetrahydrofolate in subjects. associated gastrointestinal side effects.
  • the compound IV and its pharmaceutically acceptable salts can be administered 0.5-24 hours before the administration of the fluorouracil, oxaliplatin, irinotecan and tetrahydrofolate, and the compound IV and its pharmaceutically acceptable salts
  • the salt can be administered by injection or orally, and the dosage of the compound IV and its pharmaceutically acceptable salt can be about 100 mg/kg-about 150 mg/kg.
  • compound IV and pharmaceutically acceptable salts thereof can prevent, alleviate and/or treat gastrointestinal side effects associated with topotecan in subjects.
  • compound IV and pharmaceutically acceptable salts thereof can prevent, relieve and/or treat gastrointestinal side effects associated with the combined use of gemcitabine and carboplatin in subjects.
  • compound II and pharmaceutically acceptable salts thereof can prevent, alleviate and/or treat fluorouracil-related gastrointestinal side effects in subjects.
  • the compound II and a pharmaceutically acceptable salt thereof can be administered 0.5-24 h before the administration of the fluorouracil, and the compound II and a pharmaceutically acceptable salt thereof can be administered by injection (for example, intraperitoneal injection or intramuscular injection). Injection), the dosage of the compound II and its pharmaceutically acceptable salt can be about 50mg/kg-about 150mg/kg.
  • compound II and its pharmaceutically acceptable salts can prevent, relieve and/or treat gastrointestinal side effects associated with the combination of fluorouracil, oxaliplatin, irinotecan and tetrahydrofolate in subjects .
  • the compound II and its pharmaceutically acceptable salts can be administered 0.5-24 hours before the combined administration of fluorouracil, oxaliplatin, irinotecan and tetrahydrofolic acid, and the compound II and its pharmaceutically acceptable salts
  • the salts of Compound II and its pharmaceutically acceptable salts can be administered orally or by injection, and the dosage of the compound II and its pharmaceutically acceptable salts can be about 100 mg/kg-about 150 mg/kg.
  • Compound II and pharmaceutically acceptable salts thereof can prevent, relieve and/or treat oxaliplatin-related gastrointestinal side effects in subjects.
  • the compound II and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of oxaliplatin, and the compound II and a pharmaceutically acceptable salt thereof can be administered by injection.
  • the dosage of II and its pharmaceutically acceptable salts can be about 100 mg/kg to about 150 mg/kg.
  • compound II and its pharmaceutically acceptable salts can prevent, relieve and/or treat gastrointestinal side effects associated with the combination of fluorouracil, oxaliplatin, irinotecan and tetrahydrofolate in subjects .
  • the compound II and its pharmaceutically acceptable salts can be administered 0.5-24 hours before the combined administration of fluorouracil, oxaliplatin, irinotecan and tetrahydrofolic acid, and the compound II and its pharmaceutically acceptable salts
  • the salts of Compound II and its pharmaceutically acceptable salts can be administered orally or by injection, and the dosage of the compound II and its pharmaceutically acceptable salts can be about 100 mg/kg-about 150 mg/kg.
  • compound III and pharmaceutically acceptable salts thereof can prevent, alleviate and/or treat oxaliplatin-related gastrointestinal side effects in subjects.
  • the compound III and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of the oxaliplatin, and the compound III and a pharmaceutically acceptable salt thereof can be administered orally or injected , the dosage of the compound III and the pharmaceutically acceptable salt thereof may be about 100 mg/kg-about 150 mg/kg.
  • compound III and its pharmaceutically acceptable salts can prevent, alleviate and/or treat gastrointestinal side effects associated with the combination of fluorouracil, oxaliplatin, irinotecan and tetrahydrofolate in subjects .
  • the compound III and its pharmaceutically acceptable salts can be administered 0.5-24 hours before the combined administration of fluorouracil, oxaliplatin, irinotecan and tetrahydrofolic acid, and the compound III and its pharmaceutically acceptable salts
  • the salt of Compound III can be administered orally or injected, and the dosage of the compound III and its pharmaceutically acceptable salt can be about 150 mg/kg-about 200 mg/kg.
  • compound III and pharmaceutically acceptable salts thereof can prevent, relieve and/or treat fluorouracil-related gastrointestinal side effects in subjects.
  • the compound III and a pharmaceutically acceptable salt thereof can be administered 0.5-12 hours before the administration of the fluorouracil, and the compound III and a pharmaceutically acceptable salt thereof can be administered orally or by injection, the The dosage of compound III and its pharmaceutically acceptable salts can be about 100 mg/kg-about 150 mg/kg.
  • the medicament may further include one or more pharmaceutically acceptable carriers (carriers).
  • Pharmaceutically acceptable carriers may include, but are not limited to, for example, pharmaceutically acceptable liquid, gel or solid carriers, aqueous media, non-aqueous media, antimicrobial substances, isotonic substances, buffers, antioxidants , anesthetic, suspending agent/dispersing agent, chelating agent, emulsifier, diluent, adjuvant, excipient, non-toxic auxiliary substance, filler, binder, disintegrant, buffer, preservative, lubricant, flavor Agents, thickeners, colorants, emulsifiers, other components known in the art or multiple combinations of the above.
  • this application provides A method for preventing, alleviating and/or treating gastrointestinal side effects associated with chemotherapy or a pharmaceutically acceptable salt thereof.
  • the chemotherapy is fluorouracil, oxaliplatin, irinotecan (CPT-11), tetrahydrofolate, and their combinations.
  • the compound I is administered orally or Administration by injection.
  • this application provides A method for preventing, alleviating and/or treating gastrointestinal side effects associated with chemotherapy or a pharmaceutically acceptable salt thereof.
  • the chemotherapy is fluorouracil, oxaliplatin, irinotecan (CPT-11), tetrahydrofolate, and their combinations.
  • the compound II is administered orally or Administration by injection.
  • this application provides A method for preventing, alleviating and/or treating gastrointestinal side effects associated with chemotherapy or a pharmaceutically acceptable salt thereof.
  • the chemotherapy is fluorouracil, oxaliplatin, irinotecan (CPT-11), tetrahydrofolate, and their combinations.
  • the compound III is administered orally or Administration by injection.
  • this application provides A method for preventing, alleviating and/or treating gastrointestinal side effects associated with chemotherapy or a pharmaceutically acceptable salt thereof.
  • the chemotherapy is fluorouracil, oxaliplatin, irinotecan (CPT-11), tetrahydrofolate, and their combinations.
  • the compound IV is administered orally or Administration by injection.
  • the present application provides a method for preventing, alleviating and/or treating chemotherapy-related gastrointestinal side effects with the compound represented by formula I.
  • the present application provides the use of the compound represented by formula I in the preparation of drugs for preventing, alleviating and/or treating gastrointestinal side effects associated with chemotherapy.
  • the present application provides a compound represented by formula I, which is used for preventing, alleviating and/or treating gastrointestinal side effects associated with chemotherapy during preparation.
  • the chemotherapy is administered for less than 7 consecutive days.
  • the chemotherapy is administered orally or by injection.
  • the present application provides a method for preventing, alleviating and/or treating chemotherapy-related diarrhea with the compound represented by formula I.
  • the present application provides the use of the compound represented by formula I in the preparation of medicines for preventing, alleviating and/or treating diarrhea associated with chemotherapy.
  • the present application provides a compound represented by formula I, which is used for preventing, alleviating and/or treating diarrhea associated with chemotherapy in preparation.
  • the chemotherapy is administered for less than 7 consecutive days.
  • the chemotherapy is administered orally or by injection.
  • the present application provides a method for preventing, alleviating and/or treating chemotherapy-related constipation with the compound represented by formula I.
  • the present application provides the use of the compound represented by formula I in the preparation of medicines for preventing, alleviating and/or treating constipation associated with chemotherapy.
  • the present application provides a compound represented by formula I, which is used for preventing, alleviating and/or treating constipation associated with chemotherapy during preparation.
  • the chemotherapy is administered for less than 7 consecutive days.
  • the chemotherapy is administered orally or by injection.
  • Embodiment 1-201 The compound represented by formula I alleviates the effect of diarrhea caused by chemotherapeutic agents
  • mice had symptoms of diarrhea in varying degrees (as shown in Figure 1), which was similar to that seen in humans. Therefore, the model of diarrhea caused by chemotherapeutic agents in mice is a good model for simulating the diarrhea caused by chemotherapeutic agents in humans.
  • mice After one week of adaptive feeding of Balb/c mice, they were divided into groups, and the experiment was divided into a control group, a chemotherapeutic agent group, and a compound group shown in formula I, with 10 mice in each group, and the administration experiment was carried out.
  • the time and frequency are shown in Table 3.
  • Control group inject or gavage the solvent identical with the compound group shown in formula I (injection mode and time are as shown in Table 3), inject or gavage the solvent identical with chemotherapeutic agent group afterwards (administration mode is as shown in Table 3)
  • chemotherapeutic agent group inject or gavage the same solvent (administration method and time as shown in Table 3) with the compound group shown in formula I, then inject or gavage chemotherapeutic agent (type, administration method and dosage) As shown in table 3); compound group shown in formula I: inject or gavage the compound shown in formula I (administration method and time are as shown in table 3), give chemotherapeutic agent afterwards (administration method and dosage are as shown in table 3).
  • Diarrhea scoring refers to the method of Akinobu Kurita (Cancer Chemother Pharmacol 2000; 46:211-20.). Grade 0: normal stool; Grade 1: mild diarrhea, slightly wet and soft stool; Grade 2: moderate diarrhea, loose stool and mild perianal infection; Grade 3: severe diarrhea, watery stool accompanied by severe Perianal coloring (see Figure 1). The decrease in the level of diarrhea in the mice in the compound group represented by formula I compared with the average level of diarrhea in the chemotherapy agent group is regarded as effective relief.
  • Figure 1 shows typical pictures of different grades of mouse diarrhea in the chemotherapeutic agent group in Table 3, and Figure 2 shows the partial diarrhea grade results of the control group, chemotherapeutic agent group, and compound group represented by formula I in Table 3.
  • compound I, II, IV and III, or their hydrochlorides have relief in various degrees relative to the diarrhea grade of the chemotherapeutic agent group, therefore, before the chemotherapeutic agent, give compound I, II, IV and III, or their hydrochlorides are effective in relieving diarrhea caused by chemotherapeutic agents.
  • Embodiment 202-364 The compound represented by formula I relieves the constipation caused by chemotherapeutic agents
  • mice A mouse animal model was constructed, and the constipation model induced by the chemotherapeutic agent in Balb/c mice was established according to the administration mode and frequency of the chemotherapeutic agent shown in Table 4. After a few days of administration, the mice showed a decrease in the amount of stool (as shown in Figure 3), consistent with the symptoms of constipation caused by chemotherapeutic agents in humans. Therefore, the mouse chemotherapeutic-induced constipation model is a good model for chemotherapeutic-induced constipation.
  • mice were fed adaptively for one week, they were divided into groups, and the experiment was divided into a control group, a chemotherapeutic agent, and a compound group shown in formula I, with 10 mice in each group, and the administration experiment was carried out, the administration dose, mode, and time And the frequency is shown in Table 4.
  • Control group inject or gavage the solvent identical with the compound group shown in formula I (administration method and time are as shown in Table 4), then inject or intragastrically the solvent identical with chemotherapeutic agent group (administration method is as shown in Table 4)
  • Chemotherapy agent group injection or gavage with the same solvent (administration method and time as shown in Table 4) of the compound group shown in formula I, after injection or gavage chemotherapy agent (type, administration method and Dosage is shown in table 4);
  • Compound group shown in formula I inject or gavage the compound shown in formula I (administration method and time are as shown in table 4), give chemotherapeutic agent afterwards (administration method and dosage are as shown in table 4) shown in Table 4).
  • Fig. 3 has shown the typical picture of feces amount in 3 hours of control group, chemotherapeutic agent group, the compound group shown in formula I in table 4, and Fig. 4 has shown the control group, chemotherapeutic agent group, the compound shown in formula I in table 4 Group's partial stool reduction rate results.
  • compounds I, II, IV and III, or their hydrochlorides have reductions in varying degrees relative to the chemotherapy agent group stool reduction rate, therefore, compound I is given before the chemotherapy agent , II, IV and III, or their hydrochlorides can effectively relieve constipation caused by chemotherapeutic agents.
  • Embodiment 365-384 The compound represented by formula I has the effect of alleviating diarrhea caused by continuous administration of chemotherapeutic agents
  • mice After one week of adaptive feeding of Balb/c mice, they were divided into groups, and the experiment was divided into a control group, a chemotherapeutic agent group, and a compound group shown in formula I, with 10 mice in each group, and the administration experiment was carried out.
  • the time and frequency are shown in Table 5.
  • Control group inject or gavage the solvent identical with the compound group shown in formula I (administration method and time are as shown in Table 5), then inject or gavage the solvent identical with chemotherapeutic agent group (administration method is as shown in Table 5) shown);
  • chemotherapeutic agent group inject or gavage the same solvent (administration method and time as shown in Table 5) with the compound group shown in formula I, then inject or gavage chemotherapeutic agent (kind, administration method, Time and dosage are shown in Table 5);
  • Compound group shown in formula I inject or gavage the compound shown in formula I (administration mode and time are shown in Table 5), give chemotherapeutic agent (kind, administration afterwards) The way, time and dosage are shown in Table 5).
  • Diarrhea scoring refers to the method of Akinobu Kurita (Cancer Chemother Pharmacol 2000; 46:211-20.). Grade 0: normal stool; Grade 1: mild diarrhea, slightly wet and soft stool; Grade 2: moderate diarrhea, loose stool and mild perianal infection; Grade 3: severe diarrhea, watery stool accompanied by severe Perianal coloring (see Figure 1). The decrease in the level of diarrhea in the mice in the compound group represented by formula I compared with the average level of diarrhea in the chemotherapy agent group is regarded as effective relief.
  • Compounds I, II, IV and III, and their hydrochlorides have a relieving effect on the diarrhea caused by continuous administration of chemotherapeutic agents for 7 days or less than 7 days. Diarrhea caused within 7 days was significantly relieved. Compound I has no effect on the relief of diarrhea caused by continuous administration of fluorouracil for 14 days.
  • Embodiment 385-405 The effect of oral administration of the compound represented by formula I on constipation caused by continuous administration of chemotherapeutic agents
  • mice After one week of adaptive feeding of Balb/c mice, they were divided into groups, and the experiment was divided into a control group, a chemotherapeutic agent group, and a compound group shown in formula I, with 10 mice in each group, and the administration experiment was carried out.
  • the time and frequency are shown in Table 6.
  • Matched group injection or gavage the same solvent (administration mode and time as shown in Table 6) with the compound group shown in formula I by injection or gavage, then inject or gavage the same solvent (administration mode and time as shown in Table 6) with the compound group shown in formula I mode as shown in table 6);
  • chemotherapeutic agent group inject or gavage the same solvent (administration mode and time as shown in table 6) with the compound group shown in formula I, then inject or gavage chemotherapeutic agent (kind, Administration method, time and dosage are as shown in Table 6); compound group shown in formula I: inject or gavage the compound shown in formula I (administration method and time are as shown in table 6), then give chemotherapeutic agent ( The type, administration method, time and dosage are shown in Table 6).

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un composé et un procédé de traitement d'effets secondaires gastro-intestinaux associés à la chimiothérapie. Le composé concerne une utilisation d'un composé représenté par la formule I ou d'un sel pharmaceutiquement acceptable de celui-ci dans la préparation d'un médicament, le médicament étant utilisé pour prévenir, soulager et/ou traiter des effets secondaires gastro-intestinaux associés à une chimiothérapie chez un sujet. L'invention concerne également un procédé d'utilisation du composé pour traiter des effets secondaires gastro-intestinaux associés à la chimiothérapie.
PCT/CN2022/097793 2021-06-10 2022-06-09 Composé et procédé de traitement d'effets secondaires gastro-intestinaux associés à la chimiothérapie WO2022258002A1 (fr)

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CN202280041120.9A CN117545483A (zh) 2021-06-10 2022-06-09 治疗化疗相关的胃肠道副作用的化合物和方法
KR1020247000566A KR20240021214A (ko) 2021-06-10 2022-06-09 화학요법 관련 위장 부작용을 치료하기 위한 화합물 및 방법
JP2023575985A JP2024521441A (ja) 2021-06-10 2022-06-09 化学療法関連の胃腸副作用を治療するための化合物及び方法
EP22819599.6A EP4353231A1 (fr) 2021-06-10 2022-06-09 Composé et procédé de traitement d'effets secondaires gastro-intestinaux associés à la chimiothérapie

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016040858A1 (fr) * 2014-09-12 2016-03-17 G1 Therapeutics, Inc. Combinaisons et régimes posologiques pour traiter des tumeurs rb-positives
CN110325191A (zh) * 2017-02-22 2019-10-11 G1治疗公司 以较少的副作用治疗egfr-驱动的癌症
WO2020257536A1 (fr) * 2019-06-18 2020-12-24 G1 Therapeutics, Inc. Sélection de patient pour l'amélioration de l'immunité antitumorale chez des patients atteints d'un cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016040858A1 (fr) * 2014-09-12 2016-03-17 G1 Therapeutics, Inc. Combinaisons et régimes posologiques pour traiter des tumeurs rb-positives
CN110325191A (zh) * 2017-02-22 2019-10-11 G1治疗公司 以较少的副作用治疗egfr-驱动的癌症
WO2020257536A1 (fr) * 2019-06-18 2020-12-24 G1 Therapeutics, Inc. Sélection de patient pour l'amélioration de l'immunité antitumorale chez des patients atteints d'un cancer

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AKINOBU KURITA, CANCER CHEMOTHER PHARMACOL, vol. 46, 2000, pages 211 - 20
JI EUN KIM, LAB ANIM RES., vol. 32, no. 4, December 2016 (2016-12-01), pages 231 - 240
TAN ANTOINETTE R; WRIGHT GAIL S; THUMMALA ANU R; DANSO MICHAEL A; POPOVIC LAZAR; PLUARD TIMOTHY J; HAN HYO S; VOJNOVI ; ELJKO; VAS: "Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial", THE LANCET ONCOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 20, no. 11, 28 September 2019 (2019-09-28), AMSTERDAM, NL , pages 1587 - 1601, XP085886488, ISSN: 1470-2045, DOI: 10.1016/S1470-2045(19)30616-3 *
WEISS JARED, GOLDSCHMIDT JEROME, ANDRIC ZORAN, DRAGNEV KONSTANTIN H., GWALTNEY CHAD, SKALTSA KONSTANTINA, PRITCHETT YILI, ANTAL JO: "Effects of Trilaciclib on Chemotherapy-Induced Myelosuppression and Patient-Reported Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer: Pooled Results from Three Phase II Randomized, Double-Blind, Placebo-Controlled Studies", CLINICAL LUNG CANCER, CANCER INFORMATION GROUP, DALLAS, TX, US, vol. 22, no. 5, 1 September 2021 (2021-09-01), US , pages 449 - 460, XP093014118, ISSN: 1525-7304, DOI: 10.1016/j.cllc.2021.03.010 *

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